%0 Journal Article %T UDP-glucuronosyltransferase-mediated metabolic activation of the tobacco carcinogen 2-amino-9H-pyrido[2,3-b]indole %+ Department of Civil and Environmental Engineering %+ Institut de recherche en santé, environnement et travail (Irset) %+ Unité de Toxicologie des Contaminants %A Tang, Y. %A Lemaster, David %A Nauwelaers, Gwendoline %A Gu, D. %A Langouët, Sophie %A Turesky, Robert J %< avec comité de lecture %@ 0021-9258 %J Journal of Biological Chemistry %I American Society for Biochemistry and Molecular Biology %V 287 %N 18 %P 14960-14972 %8 2012 %D 2012 %R 10.1074/jbc.M111.320093 %M 22393056 %K tobacco %K carcinogen %K 2-amino-9H-pyrido[2 %K 3-b]indole %K tabac %K toxicité %K toxicologie %K carcinogenicité %K carcinogèen %Z Life Sciences [q-bio]/ToxicologyJournal articles %X 2-Amino-9H-pyrido[2,3-b]indole (AαC) is a carcinogenic heterocyclic aromatic amine (HAA) that arises in tobacco smoke. UDP-glucuronosyltransferases (UGTs) are important enzymes that detoxicate many procarcinogens, including HAAs. UGTs compete with P450 enzymes, which bioactivate HAAs by N-hydroxylation of the exocyclic amine group; the resultant N-hydroxy-HAA metabolites form covalent adducts with DNA. We have characterized the UGT-catalyzed metabolic products of AαC and the genotoxic metabolite 2-hydroxyamino-9H-pyrido[2,3- b]indole (HONH-AαC) formed with human liver microsomes, recombinant human UGT isoforms, and human hepatocytes. The structures of the metabolites were elucidated by 1H NMR and mass spectrometry. AαC and HONH-AαC underwent glucuronidation by UGTs to form, respectively, N 2-(β- D-glucosidurony1)-2-amino-9H-pyrido[2,3-b]indole (AαC-N 2-Gl) and N 2-(β-D-glucosidurony1)-2-hydroxyamino-9H-pyrido[2,3-b] indole (AαC-HON 2-Gl). HONH-AαC also underwent glucuronidation to form a novel O-linked glucuronide conjugate, O-(β-D-glucosidurony1)-2-hydroxyamino-9H-pyrido[2,3-b]indole (AαC-HN 2-O-Gl). AαC-HN 2-O-Gl is a biologically reactive metabolite and binds to calf thymus DNA (pH 5.0 or 7.0) to form the N-(deoxyguanosin-8-yl)-AαC adduct at 20-50-fold higher levels than the adduct levels formed with HONH-AαC. Major UGT isoforms were examined for their capacity to metabolize AαC and HONH-AαC. UGT1A4 was the most catalytically efficient enzyme (V max/K m) at forming AαC-N 2-Gl (0.67 μl*min -1*mg of protein -1), and UGT1A9 was most catalytically efficient at forming AαC-HN-O-Gl (77.1 μl*min -1*mg of protein -1), whereas UGT1A1 was most efficient at forming AαC-HON 2-Gl (5.0 μl*min -1*mg of protein -1). Human hepatocytes produced AαC-N 2-Gl and AαC-HN 2-O-Gl in abundant quantities, but AαC-HON 2-Gl was a minor product. Thus, UGTs, usually important enzymes in the detoxication of many procarcinogens, serve as a mechanism of bioactivation of HONH-AαC. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc. %G English %L hal-00696860 %U https://anses.hal.science/hal-00696860 %~ ANSES %~ UNIV-RENNES1 %~ UNIV-ANGERS %~ IFR140 %~ IRSET %~ IRSET-SMS %~ IRSET-CCII %~ IRSET-TREC %~ IRSET-HIAEC %~ IRSET-SMLF %~ IRSET-ERD %~ IRSET-VCER %~ IRSET-NEED %~ IRSET-TNGC %~ UR1-UFR-SVE %~ UR1-HAL %~ UR1-SDV %~ AGREENIUM %~ IRSET-5 %~ TEST-UNIV-RENNES %~ TEST-UR-CSS %~ UNIV-RENNES %~ UR1-BIO-SA %~ TEST3-HALCNRS